Wednesday, April 20, 2011

Are we finally getting thE kNaCk of edema in nephrosis?

Mechanisms of edema formation in nephrotic syndrome (NS) are controversial. The traditional underfill hypothesis has come under heavy fire, and there are now many clinical and experimental observations that contradict it. The overfill hypothesis has now captured the zeitgeist. It postulates that sodium retention in many patients with NS is caused by an intrinsic renal defect in sodium excretion, which in turn causes an expansion of plasma volume. However, the exact mechanism of sodium retention has not been clearly elucidated and many renal sodium transporters have been implicated.

One recent paper by Svenningsen et al suggests that the epithelial sodium channel (ENaC) might be strongly implicated. Most of our understanding of the molecular mechanisms of sodium retention in NS is derived from the puromycin aminonucleoside (PAN) mouse model, which resembles minimal change disease. They found that urine of PAN nephrotic rats increased ENaC currents and amiloride abolished them. Proteolytic cleavage has a major role in regulating the activity of these channels by increasing their open probability. Specific proteases have been shown to activate ENaC by cleaving different channel subunits at specific sites within their extracellular domains. They found that plasminogen and/or plasmin were the serine proteases responsible for ENaC activation in nephrotic urine. The urine of nephrotic rats contained both substances, but the plasma from these animals only contained plasminogen, suggesting that plasmin was formed in the urine in situ and was not filtered out of the plasma. Svenningsen et al also observed that cortical collecting duct cells of nephrotic rats had urokinase activity which was directly responsible for the conversion of filtered plasminogen into plasmin. Another important observation was that amiloride not only blocks ENaC but also inhibits urokinase. Significantly, Svenningsen et al were able to reproduce all of the previously described experiments with urine from patients with NS.

These findings suggest a novel mechanism of edema in NS: plasminogen present in plasma is filtered through the defective glomerular barrier of NS and it is then converted into plasmin by the action of urokinase present in the cortical collecting duct. Plasmin then activates ENaC by proteolysis, resulting in sodium retention with the subsequent appearance of edema. More studies are needed, but this could be an important breakthrough.

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